The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

Abstract

RecQ-like helicases are a highly conserved family of proteins which are critical for preserving genome integrity. Genome instability is considered a hallmark of cancer and mutations within three of the five human RECQ genes cause hereditary syndromes that are associated with cancer predisposition. The human RecQ-like helicase BLM has a central role in DNA damage signaling, repair, replication, and telomere maintenance. BLM and its budding yeast orthologue Sgs1 unwind double-stranded DNA intermediates. Intriguingly, BLM functions in both a pro- and anti-recombinogenic manner upon replicative damage, acting on similar substrates. Thus, BLM activity must be intricately controlled to prevent illegitimate recombination events that could have detrimental effects on genome integrity. In recent years it has become evident that post-translational modifications (PTMs) of BLM allow a fine-tuning of its function. To date, BLM phosphorylation, ubiquitination, and SUMOylation have been identified, in turn regulating its subcellular localization, protein-protein interactions, and protein stability. In this review, we will discuss the cellular context of when and how these different modifications of BLM occur. We will reflect on the current model of how PTMs control BLM function during DNA damage repair and compare this to what is known about post-translational regulation of the budding yeast orthologue Sgs1. Finally, we will provide an outlook towards future research, in particular to dissect the cross-talk between the individual PTMs on BLM.

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

“…Indeed, recent studies have highlighted roles for post-translational modifications (PTMs) of BLM, including phosphorylation, SUMOylation, and ubiquitination, to mediate fine-tuning of its function (for review, see Bohm and Bernstein 2014). Both BLM and Sgs1 are regulated by PTMs, including SUMOylation (Bohm and Bernstein 2014), and some of these modifications have been linked to changes in the localization in response to different types of DNA damage (Eladad et al 2005;Ouyang et al 2009;Bohm et al 2015). However, no reports to date have explained how these modifications lead to the altered localization and whether they affect the intrinsic function of this RecQ helicase.…”

Disruption of SUMO-targeted ubiquitin ligases Slx5–Slx8/RNF4 alters RecQ-like helicase Sgs1/BLM localization in yeast and human cells

“…Post-translational modification by SUMO and/or ubiquitin is important for regulation of many DSB repair proteins including BLM and Sgs1 [20-22, 62, 76, 85]. Interestingly, we find that upon deletion of SLX8 , the number of Sgs1 foci significantly increases, both spontaneously and with damage (Figure 5A, B).…”

“…Both budding yeast Sgs1 as well as the mammalian RecQ-like helicase BLM function to either promote or repress HR depending on the cell cycle stage during which the DNA damage occurs, as well as the type of damage incurred [1]. One way to regulate protein activity is through its localization, as well as its post-translational modification [22]. Recent studies show that the activity of the mammalian homolog BLM is regulated by different forms of post-translational modification, which in turn affect its localization and protein-protein interactions [20-22, 76].…”

“…One way to regulate protein activity is through its localization, as well as its post-translational modification [22]. Recent studies show that the activity of the mammalian homolog BLM is regulated by different forms of post-translational modification, which in turn affect its localization and protein-protein interactions [20-22, 76]. In contrast, no mechanism of regulation by alteration of subcellular localization has been reported for the yeast RecQ-like helicase Sgs1.…”

“…One way to regulate RecQ-like helicases upon DNA damage is through their subcellular localization. For example, BLM is normally localized in PML bodies, but upon replicative damage BLM is SUMOylated and subsequently re-localized into nuclear DNA damage foci [20-22]. Although the yeast Sgs1 protein can form a nuclear focus [19, 23], it remains unknown if changes in subcellular localization of Sgs1 foci occur upon DNA damage.…”